Cancer is one of the leading causes of deaths worldwide. In the US alone, more than 1 million cases of various types of cancers are diagnosed each year and more than half million people die due to cancer. Accurate and early diagnosis and treatment of cancer is paramount to improve survival and quality of life. Tumor markers with diagnostic and prognostic significance can help achieve these goals and because tumors exhibit significant tumor heterogeneity, therefore, multiple tumor markers can facilitate accurate and early detection. Also, within a tumor type, one or more tumor markers can serve to sub-classify a subset of tumor and predicts its behavior. Thus, cancer markers that can facilitate accurate cancer diagnosis in general and detection at early stages in particular are urgently needed for all types of cancers. In this context, genes and their protein products differentially expressed between normal and cancer tissues have the potential to serve as important tumor markers. One of the major problems in cancer therapeutics is that the existing cancer drugs affect cancer as well as normal cells. Therefore, better therapeutic approaches are urgently needed to selectively target cancer cells but spare normal cells. In this regard, tumor markers as cancer-specific molecules linked to cancer cell growth and survival can provide very valuable insight into developing newer therapeutic strategies. For example, molecules with anti-tumor potential whose expression is deregulated in cancers can serve as important cancer diagnostic and prognostic markers on the one hand and targets to develop novel cancer therapeutics on the other. These molecules with diagnostic and prognostic potential can also predict patients' response to therapy.
Exposure to environmental agent such as UV radiation has also been linked to melanoma development. Melanoma is considered to be the highly aggressive malignancy affecting the skin (see ref. 1 and references cited therein). Melanoma arises in melanocytes and can be classified into various types including cutaneous, acral, mucosal and uveal melanomas (1). The cutaneous type is the most common and affects skin and has a predominant association with exposure to UV (1-3). This variety can be further subdivided into chronic sun-damage (CSD) melanoma and non-chronic sun-damage (non-CSD) melanoma (2, 3). The acral type affects skin of palms, soles and the area underneath fingernails or toenails. As the name implies, the mucosal variety occurs in mucosal tissues whereas the uveal type affects melanocytes in other organs for example, in iris of the eye. It is believed that the acral, mucosal and uveal types are not linked to UV exposure (1-3). Although the molecular pathogenesis of malignant melanoma remains to be fully investigated, mutations in BRAF gene that encodes a serine threonine kinase have been found in approximately 45% of the cases (1) of cutaneous (non-CSD) melanoma. In the case of mucosal, uveal and CSD varieties, the incidence of BRAF mutations is reported to be lower. Point mutations in NRAS have also been reported for non-CSD melanoma, while aberrations in KIT receptor tyrosine kinase have been found in CSD, mucosal and acral types of melanomas (1). Not all melanomas, however, harbor mutations in BRAF or NRAS or aberrations in KIT receptor-mediated signaling (4, 5). Therefore, further studies are needed to identify additional molecules that are linked to melanoma development and/or progression. Such molecules are expected to prove very valuable for better understanding of melanoma pathogenesis and can also serve as (i) markers for improved diagnosis and prognosis and (ii) targets to develop novel therapeutics.
Further approaches to manage melanoma are urgently needed. Dacarbazine (DTIC) is a commonly used anticancer drug for advanced malignant melanoma but response rate remains low and tumors initially responding to drug eventually acquire resistance to DTIC (6, 7). Cisplatin is another anticancer drug and its use in combination with other therapeutics is being explored as an alternative strategy to manage melanoma (8).
More recently, FDA has approved vemurafenib (PLX4032) for the treatment of malignant melanoma that harbor BRAF mutation (BRAFV600E is the most common oncogenic mutation that activates this kinase and about 45-50% of melanoma harbor such mutation) (9, 10). Vemurafenib does not work in melanomas that harbor wild type BRAF. Another limitation of vemurafenib is that some melanomas although harbor BRAF mutation do not respond to vemurafenib (inherent resistance) while others initially respond but later acquire resistance (9, 11, 12). The molecular basis for acquisition to vemurafenib resistance is believed to be multifactorial in nature and remains to be fully investigated (12).
Citation or identification of any reference in Section 2, or in any other section of this application, shall not be considered an admission that such reference is available as prior art to the present invention.